Tuberculosis (TB) in children is a major global public health challenge. It is estimated that about 15 -20% of the global TB caseload occur in children < 15 years old. Children are also highly susceptible to the dual epidemics of human immunodeficiency virus (HIV) and TB. HIV-infected children are at a higher risk of developing active TB and TB-related death. The treatment of TB, as well as TB/HIV coinfection in children is complicated by poor drug absorption, drug-drug interactions, high pill burden and lack of appropriate formulations. In addition, dosage recommendations for children are often extrapolated from pharmacokinetic (PK) studies in adults. Consequently, the recommended dosages of the anti-TB and antiretroviral medications have been associated with a high frequency of sub-therapeutic plasma concentrations. The lack of pediatric PK data for commonly prescribed medications in children with TB and TB/HIV coinfection represents a major obstacle to the safe and effective treatment of these conditions in children. Our long-term goal is to develop a multidisciplinary research program to study the PK of available and new anti-TB and anti-HIV medications in children in sub-Saharan Africa. The objective of this proposal is to determine the PK of the first-line anti-TB and anti-HIV drugs, as well as characterize the factors associated with variable PK and drug-drug interactions in children in Ghana, West Africa. Our overarching hypothesis is that previous studies have underestimated the effect of developmental and genetic differences in drug metabolism, drug-drug interactions, as well as the risk for suboptimal drug concentrations in children. Our hypotheses will be pursued through three specific aims. Aim 1 will determine whether the WHO recommended increased dosages of isoniazid, rifampin, pyrazinamide and ethambutol administered to African children with active TB infection (with or without HIV co- infection) achieve adult-equivalent therapeutic drug concentrations, and identify possible predictors of sub- therapeutic concentrations. Aim 2 will determine whether rifampin-containing TB therapy induces drug clearance substantially in young TB/HIV co-infected children resulting in reduced nevirapine exposure as compared to children receiving nevirapine therapy without anti-TB therapy. Aim 3 will determine whether rifampin-containing TB therapy significantly influence efavirenz concentrations in older TB/HIV co-infected children compared to HIV-infected children treated with a similar regimen in the absence of anti-TB treatment. Successful completion of the proposed studies will generate fundamental PK data for these commonly prescribed medications, as well as provide insights into predictors of the variable PK in children. Without such data, rational decisions about prescribing anti-TB and anti-HIV medications in children are not possible. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Globally, ~one million new cases of TB (with or with HIV coinfection) and ~130,000 TB deaths occur in children each year. The treatment of TB, and TB/HIV coinfection in children can reduce the high death rates, but it is complicated by poor drug absorption, drug-drug interactions, and lack of appropriate drug formulations. Currently, there is lack of adequate pharmacology data for commonly prescribed medications in children with TB and TB/HIV coinfection in sub-Saharan Africa, the most affected region. This situation represents a major obstacle to the safe and effective treatment of these conditions in children. Our long-term goal is to develop a multidisciplinary research program to study the pharmacology of available and new anti-TB and anti-HIV medications in children in West Africa. In the long-term, we hope that our research will provide urgently needed evidence to guide rational decisions about prescribing anti-TB and anti-HIV medications in children. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page